Pyrido 3,2,1-I,J! 3,1!benzoxazine derivatives

ABSTRACT

Disclosed are pyrido 3,2,1-i,j! 3,1!benzoxazine compounds of the formula (I): ##STR1## wherein z represents a radical having the formula: ##STR2## wherein B represents --CH 2  --, --O-- or a direct bond; and the other variables in formula (I) and Z are as described herein. The compounds have antibacterial properties and also disclosed are antibacterial compositions containing them and methods of using them to prevent or combat bacterial infections. Methods for preparing the compounds are also disclosed.

This application has been filed under 35 USC 371 as National Stageapplication of PCT/EP95/02510 filed Jun. 28, 1995.

The invention relates to new pyrido 3,2,1-i,j! 3,1!benzoxazinederivatives, to processes for their preparation, and to antibacterialcompositions comprising them.

It has already been disclosed that pyridobenzoxazinecarboxylic acidshave an antibacterial activity. Examples can be found in EP-O 373 531.

There have now been found compounds of the general formula (I) ##STR3##in which R¹ represents hydrogen or C₁ -C₄ -alkyl which is optionallysubstituted by hydroxyl or halogen,

R² independently of R¹ represents hydrogen or methyl,

R³ represents hydrogen or C₁ -C₄ -alkyl,

R^(3') independently of R³ represents hydrogen or methyl,

R⁴ represents hydrogen, alkyl having 1 to 4 carbon atoms which isoptionally substituted by hydroxyl, methoxy, amino, methylamino ordimethylamino, or represents (5-methyl-2-oxo-1,3-dioxol-4-yl)-methyl,

X¹ represents hydrogen or halogen,

Z represents radicals of the structures ##STR4## in which R⁷ representshydrogen, hydroxyl, --NR¹⁰ R¹¹, hydroxymethyl, --CH₂ --NR¹⁰ R¹¹,carboxyl, methoxycarbonyl or ethoxycarbonyl,

where

R¹⁰ represents hydrogen, C₁ -C₃ -alkyl which is optionally substitutedby hydroxyl, or represents alkoxycarbonyl having 1 to 4 C atoms in thealkoxy moiety, or C₁ -C₃ -acyl,

R¹¹ represents hydrogen or methyl,

R⁸ represents hydrogen, straight-chain or branched C₁ -C₃ -alkyl orcyclopropyl,

R⁹ represents hydrogen or methyl,

R⁶ represents hydrogen or methyl,

R⁵ represents hydrogen, methyl or radicals of the structures--CH═CH--CO₂ R⁵, --CH₂ --CH₂ --CO₂ R^(5'), --CH₂ --CO--CH₃, --CH₂ --CH₂--CN,

R^(5') represents methyl or ethyl, and

B represents --CH₂ --, O or a direct bond.

The compounds of the formula (I) can exist in the form of racemates orenantiomerically pure compounds, in the form of their pharmaceuticallyutilizable hydrates and acid addition salts, and in the form of theiralkali metal salts, alkaline earth metal salts, silver salts andguanidinium salts.

The compounds of the formula (I) are obtained when compounds of theformula (II) ##STR5## in which R¹, R², R³, R^(3'), R⁴ and X¹ have theabovementioned meaning and

X² represents halogen, in particular fluorine or chlorine, are reactedwith compounds of the formula (III)

    Z--H                                                       (III)

in which

Z has the abovementioned meaning, if appropriate in the presence of acidscavengers.

Compared with known representatives of this structural type, thecompounds according to the invention have a more powerful antibacterialaction, in particular in the Gram-positive sector. They are thereforesuitable as active compounds for human and veterinary medicine,veterinary medicine also including the treatment of fish for the therapyor the prevention of bacterial infections.

Preferred compounds of the formula (I) are those in which

R¹ represents hydrogen or C₁ -C₃ -alkyl which is optionally substitutedby hydroxyl,

R² independently of R¹ represents hydrogen or methyl,

R³ represents hydrogen, methyl or ethyl,

R^(3') independently of R³ represents hydrogen or methyl,

R⁴ represents hydrogen, alkyl having 1 to 4 carbon atoms which isoptionally substituted by hydroxyl, methoxy, amino, methylamino ordimethylamino, or represents (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl,

X¹ represents hydrogen, fluorine or chlorine,

Z represents radicals of the structures ##STR6## in which R⁷ representshydrogen, hydroxyl, --NR¹⁰ R¹¹, hydroxymethyl or --CH₂ --NR¹⁰ R¹¹,

where

R¹⁰ represents hydrogen, C₁ -C₂ -alkyl which is optionally substitutedby hydroxyl, or represents alkoxycarbonyl having 1 to 4 C atoms in thealkoxy moiety, or C₁ -C₃ -acyl,

R¹¹ represents hydrogen or methyl,

R⁸ represents hydrogen, straight-chain or branched C₁ -C₃ -alkyl orcyclopropyl,

R⁹ represents hydrogen or methyl,

R⁵ represents hydrogen or methyl,

R⁶ represents hydrogen, and

B represents --CH₂ --, O or a direct bond,

and their pharmaceutically utilizable hydrates and acid addition salts,as well as their alkali metal salts, alkaline earth metal salts, silversalts and guanidinium salts.

Particularly preferred compounds of the formula (I) are those in which

R¹ represents hydrogen or methyl,

R² hydrogen,

R³ represents methyl or ethyl,

R^(3') represents hydrogen or methyl,

R⁴ represents hydrogen, methyl or ethyl,

X¹ represents fluorine,

Z represents radicals of the structures ##STR7## in which R⁷ representshydrogen, hydroxyl, --NR¹⁰ R¹¹, hydroxymethyl or --CH₂ --NR¹⁰ R¹¹,

where

R¹⁰ represents hydrogen, methyl, alkoxycarbonyl having 1 to 4 C atoms inthe alkoxy moiety or C₁ -C₃ -acyl,

R¹¹ represents hydrogen or methyl,

R⁸ represents hydrogen, straight-chain or branched C₁ -C₃ -alkyl orcyclopropyl,

R⁶ represents hydrogen,

R⁹ represents hydrogen or methyl,

R⁵ represents hydrogen or methyl, and

B represents --CH₂ --, O or a direct bond,

and their pharmaceutically utilizable hydrates and acid addition salts,as well as their alkali metal salts, alkaline earth metal salts, silversalts and guanidinium salts.

The following compounds of the formula (I) may be mentionedspecifically:

    __________________________________________________________________________     ##STR8##                                                                     R.sup.3 '                                                                          R.sup.3                                                                           R.sup.4     Z            X                                           __________________________________________________________________________    H    Me  H                                                                                          ##STR9##    F                                           H    Me  H                                                                                          ##STR10##   F                                           H    Me  H                                                                                          ##STR11##   F                                           H    Me  Et                                                                                         ##STR12##   F                                           H    Et  H                                                                                          ##STR13##   F                                           Me   Me  H                                                                                          ##STR14##   F                                           Me   Me  H                                                                                          ##STR15##   F                                           CH.sub.2 OH                                                                        Me  H                                                                                          ##STR16##   F                                           H    H   H                                                                                          ##STR17##   F                                           H    H   ethyl                                                                                      ##STR18##   F                                           H    H   H                                                                                          ##STR19##   F                                           H    H   H                                                                                          ##STR20##   F                                           CH.sub.3                                                                           H   ethyl                                                                                      ##STR21##   F                                           H    H   CH.sub.2 CH.sub.2 NH.sub.2                                                                 ##STR22##   F                                           H    H   CH.sub.2 CH.sub.2 OCH.sub.3                                                                ##STR23##   F                                           CH.sub.3                                                                           H   H                                                                                          ##STR24##   F                                           CH.sub.3                                                                           CH.sub.3                                                                          H                                                                                          ##STR25##   F                                           H    CH.sub.3                                                                          ethyl                                                                                      ##STR26##   F                                           H    CH.sub.3                                                                          CH.sub.2 CH.sub.2 NH.sub.2                                                                 ##STR27##   F                                           H    CH.sub.3                                                                          CH.sub.2 CH.sub.2 OCH.sub.3                                                                ##STR28##   F                                           H    H   ethyl                                                                                      ##STR29##   F                                           CH.sub.3                                                                           H   H                                                                                          ##STR30##   F                                           CH.sub.3                                                                           CH.sub.3                                                                          H                                                                                          ##STR31##   F                                           H    Me  H                                                                                          ##STR32##   F                                           H    Me  H                                                                                          ##STR33##   F                                           H    Me  H                                                                                          ##STR34##   F                                           H    Et  H                                                                                          ##STR35##   F                                           Me   Me  H                                                                                          ##STR36##   F                                           CH.sub.2 OH                                                                        Me  H                                                                                          ##STR37##   F                                           H    Me  H                                                                                          ##STR38##   F                                           H    Me  H                                                                                          ##STR39##   F                                           H    Me  H                                                                                          ##STR40##   F                                           H    Me  H                                                                                          ##STR41##   F                                           H    Me  H                                                                                          ##STR42##   F                                           H    Me  H                                                                                          ##STR43##   F                                           H    Me  H                                                                                          ##STR44##   F                                           H    Me  H                                                                                          ##STR45##   F                                           H    Me  H                                                                                          ##STR46##   F                                           H    Me  H                                                                                          ##STR47##   F                                           H    Me  H                                                                                          ##STR48##   F                                           H    Me  H                                                                                          ##STR49##   F                                           H    Me  H                                                                                          ##STR50##   F                                           Me   Me  H                                                                                          ##STR51##   F                                           Me   Me  H                                                                                          ##STR52##   F                                           CH.sub.2 OH                                                                        Me  H                                                                                          ##STR53##   F                                           CH.sub.2 OH                                                                        Me  H                                                                                          ##STR54##   F                                           CH.sub.2 OH                                                                        Me  H                                                                                          ##STR55##   F                                           H    Et  H                                                                                          ##STR56##   F                                           H    Et  H                                                                                          ##STR57##   F                                           H    Me  Et                                                                                         ##STR58##   F                                           H    Me  Et                                                                                         ##STR59##   F                                           __________________________________________________________________________

If, for example, 9,10-difluoro-3-methyl-7-oxo-1H, 3H, 7H-pyrido1,2,3-d,e!- 3,1!benzoxazine-6-carboxylic acid and 2,8-diazabicyclo4.3.0!nonane are used for the preparation of compounds of the formula(I), the course of the reaction can be represented by the followingequation: ##STR60##

The compounds of the formula (II) which are used as starting compoundsare known or can be prepared by known processes. If appropriate, theycan be employed in the form of the racemates, enantiomers or purediastereomers.

Examples which may be mentioned are:

9,10-difluoro-3-methyl-7-oxo- 1H,3H,7H-pyrido- 3,2,1-i,j!3,1!benzoxazine-6-carboxylic acid

9,10-difluoro-3-ethyl-7-oxo-1H,3H, 7H-pyrido- 3,2,1-i,j! 3,1!benzoxazine-6-carboxylic acid

9,10-chloro-3-methyl-7-oxo-1H,3H,7H-pyrido- 3,2,1-i,j!3,1!benzoxazine-6-carboxylic acid

9,10-difluoro-3-dimethyl-7-oxo- 1H,3H,7H-pyrido- 3,2,1-i,j!3,1!benzoxazine-6-carboxylic acid

ethyl 9,10-difluoro-3-methyl-7-oxo- 1H,3H,7H-pyrido- 3,2,1-i,j!3,1!benzoxazine-6-carboxylate

The amines of the formula (III) which are used as starting compounds areknown. Chiral amines can be employed in the form of the racemates aswell as enantiomerically or diastereomerically pure compounds.

Examples which may be mentioned are:

2,7-diazabicyclo 3.3.0!octane

2-methyl-2,7-diazabicyclo 3.3.0!octane

2,8-diazabicyclo 4.3.0!nonane

2-methyl-2,8-diazabicyclo 4.3.0!nonane

2-oxa-5,8-diazabicyclo 4.3.0!nonane

5-methyl-2-oxa-5,8-diazabicyclo 4.3.0!nonane

2-amino-8-azabicyclo 4.3.0!non-3-ene

2-methylamino-8-azabicyclo 4.3.0!non-3-ene

4-methyl-2-methylamino-8-azabicyclo 4.3.0!non-3 -ene

5-methyl-2-methylamino-8-azabicyclo 4.3.0!non-3-ene

2-dimethylamino-8-azabicyclo 4.3.0!non-3 -ene

2-ethylamino-8-azabicyclo 4.3.0!non-3-ene

2-methylaminomethyl-8-azabicyclo 4.3.0!non-3-ene

2-hydroxy-8-azabicyclo 4.3.0!non-3-ene

5-isopropyl-2-methylamino-8-azabicyclo 4.3.0!non-3 -ene

2-amino-5-isopropyl-8-azabicyclo 4.3.0!non-3 -ene

2-amino-5-methyl-8-azabicyclo 4.3.0!non-3-ene

2-hydroxymethyl-8-azabicyclo 4.3.0!non-3-ene

2-amino-5-cyclopropyl-8-azabicyclo 4.3.0!non-3-ene

8-azabicyclo 4.3.0!non-2-ene

ethyl 8-azabicyclo 4.3.0!non-4-ene-2-carboxylate

2-hydroxymethyl-8-azabicyclo 4.3.0!non-4-ene

2-amino-8-azabicyclo 4.3.0!non-4-ene

2-ethyl oxycarbonylamio-8-azabicyclo 4.3.0!on-4-ene

2-tert-butyloxycarbonylamino-8-azabicyclo 4.3.0!non-4- ene

2-benzyloxycarbonylamino-8-azabicyclo 4.3.0!non-4-ene

2-allyloxycarbonylarninomethyl-8-azabicyclo 4.3.0!non-4-ene

2-aminomethyl-8-azabicyclo 4.3.0!non -4-ene

2-ethyloxycarbonylaminomethyl-8-azabicyclo 4.3.0!non-4-ene

2-tert-butyloxycarbonylaminomethyl-8-azabicycl 4.3.0!non-4-ene

2-methylamino-8-azabicyclo 4.3.0!non-4-ene

2-ethylamino-8-azabicyclo 4.3.0!non-4-ene

2-cyclopropylamino-8-azabicyclo 4.3.0!non-4-ene

2-dimethylamino-8-azabicyclo 4.3.0!non-4-ene

2- (2-hydroxyethyl)-amino!-8-azabicyclo 4.3.0!non-4-ene

2-amino-1-methyl-8-azabicyclo 4.3.0!non-4-ene

2-amino-2-methyl-8-azabicyclo 4.3.0!non-4-ene

2-amino-3-methyl-8-azabicyclo 4.3.0!non-4-ene

2-ethyloxycarbonylamino-3-methyl-8-azabicyclo 4.3.0!non-4-ene

2-tert-butyl oxycarbonylamino-3 -methyl-8-azabicyclo 4.3.0!non-4-ene

2-benzyloxycarbonylamino-3-methyl-8-azabicyclo 4.3.0!non-4-ene

2-allyloxycarbonylaminomethyl-3-methyl-8-azabicyclo 4.3.0!non-4-ene

2-amino-4-methyl-8-azabicyclo 4.3.0!non-4-ene

2-amino-5-methyl-8-azabicyclo 4.3.0!non-4-ene

2-amino-6-methyl-8-azabicyclo 4.3.0!non-4-ene

2-amino-7-methyl-8-azabicyclo 4.3.0!non-4-ene

2-amino-9-methyl-8-azabicyclo 4.3.0!non-4-ene

The substituted 8-azabicyclo 4.3.0!non-4-enes and 8-azabicyclo4.3.0!non-2-enes as well as their preparation are disclosed in DE-OS(German Published Specification) 4 230 804.

They are obtained by reacting suitable dienes with suitable dienophilesin a Diels-Alder reaction, which can be carried out intermolecularly orintramolecularly, and, if appropriate, subsequently carrying out furtherchemical reactions so as to construct the pyrrolidine ring, ifappropriate, and to introduce substituents which are desired for theirbiological action and, as the last step, eliminating the protectivegroup from the pyrrolidine nitrogen.

If the Diels-Alder reaction is carried out intramolecularly, compoundsof the formula (1) or (2) ##STR61## in which R⁸ and R⁹ have theabovementioned meaning and

P represents a protective group (for example allyl, acyl, carbamoyl ortrityl), and

Z represents hydrogen, a carboxyl, carboxylate or carboxamide group, CNor NO₂,

are reacted to give compounds of the formula (3) starting from (1)! or(4) starting from (2)! ##STR62## in which R⁸, R⁹, P and Z have theabovementioned meanings.

Some intramolecular Diels-Alder reactions of a similar type are known:J. M. Mellor, A. M. Wagland; J. Chem. Soc. Perkin I, 997-1005 (1989); W.R. Roush, S. E. Hall; J. Am. Chem. Soc. 103, 5200 (1980); E. Ciganek;Organic Reactions 32, 1-374 (1984). However, these publications fail tomention protective groups which are not only suitable for the reactionbut can also be eliminated subsequently without problems.

If the Diels-Alder reaction is carried out intermolecularly, dienes ofthe formula (5) are reacted with dienophiles of the formula (6) to givecompounds of the formula (7), and, if appropriate after modification ofgroups Z¹ and Z², for example conversion of a cyclic carboxylicanhydride into a diester with elimination of the protective groups P¹ orP¹ and P², subjected to a cyclization reaction to give the lactams ofthe formula (8). ##STR63## In formula (5), (6), (7) and (8), R⁸ and R⁹have the abovementioned meaning,

P¹ represents an acyl or carbamoyl protective group if

P² represents hydrogen, or

P¹ together with P² forms an imide,

Z¹ and Z² represent hydrogen, carboxyl, carboxylate or carboxamidegroups, CN or NO₂, where at least one of the two groups Z¹ or Z² must bea carboxylate group or a carboxamide group or CN, or Z¹ and Z² togetherform a bridge, so that a cyclic carboxylic anhydride is formed.

Preferred protective groups P, P¹ and P² are those protective groups inwhich, under the conditions used for their elimination, cyclization tothe lactam and, if appropriate, an esterification of a second, as yetfree carboxyl function with the alcohol used as the solvent takes place,in such a manner that all reaction steps can be carried out in a one-potreaction and that uncontrolled conversion of starting substances, ifappropriate diastereomerically and enantiomerically pure startingsubstances, into isomer mixtures which cannot be separated, or aredifficult to separate, does not take place.

Examples which may be mentioned are:

1. the tert-butyloxycarbonyl protective group (eliminated using aqueousor alcoholic acids)

2. the phthalimido protective group (aminolysis using primary amines inaqueous or anhydrous alcohols as solvent)

The reaction of the compounds of the formula (II) with compounds of theformula (III), in which the compounds (III) may also be employed in theform of their salts, such as, for example, the hydrochlorides, ispreferably carried out in a diluent such as dimethyl sulphoxide,N,N-dimethylformamide, N-methylpyrrolidone, hexamethyl-phosphorictriamide, sulpholane, acetonitrile, water, an alcohol such as methanol,ethanol, n-propanol, isopropanol, glycol monomethyl ether or pyridine.Mixtures of these diluents can also be used.

Acid binders which can be used are all customary inorganic and organicacid-binding agents. These preferably include the. alkali metalhydroxides, alkali metal carbonates, organic amines and amidines.Substances which may be mentioned specifically as being particularlysuitable are: triethylamine, 1,4-diazabicyclo 2.2.2!octane (DABCO),1,8-diazabicyclo 5.4.0!undec-7-ene (DBU) or excess amine (III).

The reaction temperatures can be varied within a substantial range. Ingeneral, the process is carried out between approximately 20° and 200°C., preferably between 80° and 180° C.

The reaction can be carried out under atmospheric pressure, but alsounder elevated pressure. In general, the process is carried out atpressures of between 1 bar and 100 bar, preferably between 1 and 10 bar.

When carrying out the process according to the invention, 1 to 15 mol,preferably 1 to 6 mol, of the compound (III) are employed per mole ofthe compound (II).

During the reaction, free amino groups may be protected by a suitableamino protective group, for example by the tert-butoxycarbonyl radical,and, after the reaction has ended, set free again by treatment with asuitable acid such as hydrochloric acid or trifluoroacetic acid (seeHouben-Weyl, Methoden der Organischen Chemie Methods in OrganicChemistry!, Volume E4, page 144 (1983); J. F. W. Mc Omie, ProtectiveGroups in Organic Chemistry (1973), page 43).

The esters according to the invention are obtained by reacting an alkalimetal salt of the basic carboxylic acid which can optionally beprotected on the N atom by a protective group, such as thetert-butoxycarbonyl radical, with suitable halogenoalkyl derivatives ina solvent such as dimethylformamide, dimethylacetamide,N-methylpyrrolidone, dimethyl sulphoxide or tetramethylurea, attemperatures from approximately 0° to 100° C., preferably 0° to 50° C.

The acid addition salts of the compounds according to the invention areprepared in the customary manner, for example by dissolving the betainein a sufficient amount of aqueous acid and precipitating the salt withan organic solvent which is miscible with water, such as methanol,ethanol, acetone or acetonitrile. It is also possible to heat equivalentamounts of betaine and acid in water or an alcohol such as glycolmonoethyl ether and subsequently evaporating the solution to dryness orfiltering off with suction the salt which has precipitated.Pharmaceutically utilizable salts are to be understood as meaning, forexample, the salts of hydrochloric acid, sulphuric acid, acetic acid,glycolic acid, lactic acid, succinic acid, citric acid, tartaric acid,methanesulphonic acid, 4-toluenesulphonic acid, galacturonic acid,gluconic acid, embonic acid, glutamic acid or aspartic acid. Thecompounds according to the invention may furthermore be bound to acidicor basic ion exchangers.

The alkali metal salts or alkaline earth metal salts of the carboxylicacids according to the invention are obtained, for example, bydissolving the betaine in a substoichiometric amount of alkali metalhydroxide solution or alkaline earth metal hydroxide solution, filteringoff undissolved betaine and evaporating the filtrate to dryness.Pharmaceutically suitable are sodium salts, potassium salts or calciumsalts. The corresponding silver salts are obtained by reacting an alkalimetal salt or alkaline earth metal salt with a suitable silver salt,such as silver nitrate.

The compounds according to the invention have a powerful antibioticaction and combine low toxicity with a broad antibacterial spectrumagainst Gram-positive and Gram-negative microorganisms, in particularalso against those which are resistant to various antibiotics such as,for example, penicillins, cephalosporins, aminoglycosides, sulphonamidesand tetracyclins.

These valuable properties allow them to be used as chemotherapeuticaction in medicine and veterinary medicine as well as substances forpreserving inorganic and organic materials, in particular a wide rangeof organic materials, for example polymers, lubricants, paints, fibres,leather, paper and wood, foodstuffs and water.

The compounds according to the invention are active against a very broadspectrum of microorganisms. With their aid, Gram-negative andGram-positive bacteria and bacteria-like microorganisms can becontrolled, and the diseases caused by these pathogens can be prevented,alleviated and/or cured.

The compounds according to the invention are distinguished by animproved activity against dormant and resistant microorganisms. In thecase of dormant bacteria, that is to say bacteria which show nodetectable growth, the compounds are active at concentrations which arebelow those of similar substances. This not only refers to the amount tobe employed, but also to the speed of destruction. Such results wereobserved in Gram-positive and -negative bacteria, in particular inStaphylococcus aureus, Micrococcus luteus and Enterococcus faecalis.

The compounds according to the invention also show surprising, increasedactivity against bacteria which are classified as less sensitive tocomparable substances, in particular resistant Staphylococcus aureus andEnterococcus faecalis.

The compounds according to the invention are particularly active againstbacteria and bacteria-like microorganisms. They are thereforeparticularly suitable for the prophylaxis and chemotherapy of local andsystemic infections in human and veterinary medicine which are caused bythese pathogens.

The compounds are furthermore suitable for controlling protozoonoses andhelminthoses.

The compounds according to the invention can be used in variouspharmaceutical preparations. Preferred pharmaceutical preparations whichmay be mentioned are tablets, coated tablets, capsules, pills, granules,suppositories, injectable solutions, suspensions and emulsions,solutions, suspensions and emulsions for oral administration,furthermore pastes, ointments, gels, creams, lotions, powders andsprays.

The minimum inhibitory concentrations (MICs) were determined by serialdilution methods using Iso-Sensitest agar (Oxoid). For each testsubstance, a series of agar plates was prepared whose active compoundconcentrations decreased as the dilution was doubled. The agar plateswere inoculated using a multipoint inoculator (Denley). The culturesused for inoculation were overnight cultures of the pathogen which hadpreviously been diluted to such an extent that each inoculation pointcontained approximately 10⁴ colony-forming units. The inoculated agarplates were incubated at 37° C., and the microbial growth was read offafter approximately 20 hours. The MIC value (μg/ml) indicates the lowestactive compound concentration at which no growth was observed with thenaked eye.

The following table lists the MIC values of some of the compoundsaccording to the invention in comparison with9-fluoro-3-methyl-10-(4-methyl-1-piperazinyl)-7-oxo-1H,3H,7H-pyrido3,2,1-i,j!- 3,1!-benzoxazine-6-carboxylic acid (EP-O 373 531) asreference compound.

                  TABLE                                                           ______________________________________                                        MIC values                                                                                  Example No.                                                     Species  Strain     1      4     5     Reference                              ______________________________________                                        E. coli  Z 431 Lit  0.015  0.06  ≦0.015                                                                       0.05                                            21 Bui     4      4     4     0.05                                   Klebsiella                                                                             2363 Ge    0.06   0.12  0.12  0.5                                    pneumoniae                                                                    Salmonella                                                                             1 Fr       0.06   0.25  0.12  1                                      Enterobacter                                                                           0,4 Ge 02-33                                                                             0.25   0.12  0.12  1                                      Staphylococcus                                                                         Z 2 Lit    0.12   0.5   0.12  16                                     aureus   3781 Ge    0.12   8     0.12  128                                    Pseudomonas                                                                            BS 698 TGD 4      8     16    64                                     ______________________________________                                    

EXAMPLE 1 ##STR64## 10-(2-Amino-8-azabicyclo4,3,0!non-3-en-8-yl)-9-fluoro-3-methyl-7-oxo-1H,3H,7H-pyrido- 3,2,1-i,j!3,1!benzoxazine6-carboxylic acid

293 mg (1.04 mmol) of 9,10-difluoro-3-methyl-7-oxo-1H,3H,7H-pyrrido-3,2,1-i,j! 3,1!benzoxazine-6-carboxylic acid together with 200 mg (1.30mmol) of 2-amino-8-azabicyclo 4,3,0!non-3-ene and 156 mg (1.4 mmol) of1,4-diazabicyclo- 2,2,2!octane are heated in 1.5 ml of dimethylsulphoxide for 60 minutes at 130° C. under argon. After cooling, themixture is poured into water, the pH is brought to 7.5 using dilutehydrochloric acid, and the product is filtered off with suction. It iswashed with water and dried in the air. For purification, the product isrecrystallized from ethanol.

Yield: 150 mg (36% of theory)

Melting point: 207° C. (decomposition)

Diastereomer mixture

The following are obtained analogously:

EXAMPLE 2 ##STR65## 10-(2-Hydroxymethyl-8-azabicyclo4,3,0!non-3-en-8-yl)-9-fluoro-3-methyl-7-oxo-1H,3H,7H-pyrido- 3,2,1-i,j!3,1!benzoxazine-6-carboxylic acid

Melting point: 230° C. (decomposition)

Diastereomer mixture

EXAMPLE 3 ##STR66## 10-(2-Amino-5-isopropyl-8-azabicyclo4,3,0!non-3-en-8-yl)-9-fluoro-3-methyl-7-oxo-1H,3H,7H-pyrido- 3,2,1-i,j!3,1!benzoxazine-6-carboxylic acid

Melting point: 150° C. (decomposition)

Diastereomer mixture

EXAMPLE 4 ##STR67## 10-(2.8-Diazabicyclo4,3,0!nonan-8-yl)-9-fluoro-3-methyl-7-oxo-1H,3H,7H-pyrido- 3,2,1-i,j!3,1!benzoxazine-6-carboxylic acid

Melting point: 185° C. (decomposition)

Diastereomer mixture

EXAMPLE 5 ##STR68## 9-Fluoro-3-methyl-10-(2-methylamino-8-azabicyclo4.3.0!non-3-en-8-yl)-7-oxo-1H,3H,7H-pyrido 3,2,1-i,j!3,!benzoxazine-6-carboxylic acid

Melting point: 200° C. (decomposition)

Diastereomer mixture

EXAMPLE 6 ##STR69## 9-Fluoro-3 -methyl- 10-(2-methylamino-8-azabicyclo4.3.0!non-4-en-8yl)-7-oxo-1H,3H,7H-pyrido 3.2.1-i,j!3.1!benzoxacine-6-carboxylic acid

Melting point: 290° C. (decomposition)

Diastereomer mixture.

Preparation of the intermediates:

Example A:

8-Azabicyclo 4.3.0!non-2-ene

A.1. (E)-1-Bromo-2,4-pentadiene ##STR70##

At 0° C., introduce 84 g (1.0 mol) of 1,4-pentadien-3-ol. Add dropwisewith stirring 150 ml (≈1.3 mol) of 48% strength aqueous hydrobromic acidin such a manner that the internal temperature does not rise above 5° C.When the addition is complete, continue stirring for 1 h at roomtemperature. The organic phase is separated off and reacted furtherwithout purification.

Yield: 107-129 g (73-88% of theory)

A.2. (E)-1-(2-Propenylamino)-2,4-pentadiene ##STR71##

Introduce 228 g (4.0 mol) of 1-amino-2-propene. Add dropwise withstirring 58.8 g (0.4 mol) of (E)-1-bromo-2,4-pentadiene (title compoundof Example A.1.). Keep the internal temperature in a range of 20°-30° C.by means of cooling. Stir for 5 h at room temperature. Concentrate batchat 150 mbar. Add 20 g (0.5 mol) of sodium hydroxide, dissolved in 200 mlof water, extract the mixture twice using in each case 100 ml ofmethylene chloride, dry using sodium sulphate, add 0.1 g of4-hydroxyanisole, concentrate and distil at 40 mbar. 10-20 ppm of4-hydroxyanisole are added to stabilize the distillate.

Yield: 33-35 g (67-72% of theory)

Boiling point: 77°-82° C. at 40 mbar

¹ H NMR (CDCl₃): δ=6.07-6.48 (m, 2H); 5.64-6.07 (m, 2H); 5.00-5.27 (m,411); 3.19-3.36 ppm (m, 4H).

A.3. N- (E)-2,4-Pentadienyl!-N-(2-propenyl)-acetamide ##STR72##

Introduce 24.6 g (0.2 mol) of (E)-1-(2-propenylamino)-2,4-pentadiene(title compound of Example A.2.), dropwise add 22.4 g of aceticanhydride, and stir overnight at room temperature. Concentrate and reactfurther in the form of the crude product.

A.4. 8-Acetyl-8-azabicyclo 4.3.0!non-2-ene ##STR73##

Dissolve 33.1 g (0.2 mol) of N-(E)-2,4-pentadienyl!-N-(2-propenyl)-acetamide (title compound of ExampleA.3.) in 200 ml of xylene, pass through a vigorous stream of nitrogenfor 15 min, add 0.1 g of 4-hydroxyanisole, then reflux overnight.Concentrate and distil under a high vacuum.

Yield: 23.1 g (70% of theory based on the title compound of ExampleA.2.)

Boiling point: 88°-93° C. at 0.05 mbar

A. 5.8-Azabicyclo 4.3.0!non-2-ene ##STR74##

Reflux 16.5 g (0.1 mol) of 8-acetyl-8-azabicyclo 4.3.0!non-2-ene (titlecompound of Example A.4.) for 3 h in a mixture of 100 ml of 45% strengthsodium hydroxide solution, 50 ml of water and 100 ml of 1,2-ethanediol.After cooling, extract four times using in each case 50 ml of diethylether. Dry combined organic phases using sodium sulphate and distilunder a high vacuum.

Yield: 6.6 g (54% of theory)

Boiling point: 36°-44° C. at 0.35 mbar

¹ H NMR (CDCl₃): δ=5.79 (m, 1H); 5.74 (m, 1H); 3.02-3.17 (m, 2H);2.47-2.72 (m, 2H); 2.06-2.30 (m, 2H); 1.91-2.06 (m, 2H); 1.68 (m, 1H);1.45 ppm (m, 1H).

We claim:
 1. A compound of the formula (I): ##STR75## in which R¹represents hydrogen or C₁₋₄ -alkyl which is optionally substituted byhydroxyl or halogen;R² represents hydrogen or methyl; R³ representshydrogen or C₁₋₄ -alkyl; R^(3') represents hydrogen or methyl; R⁴represents hydrogen, C₁₋₄ -alkyl which is optionally substituted byhydroxyl, methoxy, amino, methylamino or dimethylamino, or represents(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl; X¹ represents hydrogen orhalogen; Z represents a radical of the formula: ##STR76## in which R⁷represents hydrogen, hydroxyl, --NR¹⁰ R¹¹, hydroxymethyl, --CH₂ --NR¹⁰R¹¹, carboxyl, inethoxycarbonyl or ethoxycarbonyl;in which R¹⁰represents hydrogen, C₁₋₃ -alkyl which is optionally substituted byhydroxyl, or represents C₁₋₄ -alkoxycarbonyl or C₁₋₃ -acyl- and R¹¹represents hydrogen or methyl; R⁸ represents hydrogen, straight-chain orbranched C₁₋₃ -alkyl, or cyclopropyl; R⁹ represents hydrogen or methyl;R⁶ represents hydrogen or methyl; R⁵ represents hydrogen, methyl,--CH═CH--CO₂ R^(5'), --CH₂ --CH₂ --CO₂ R^(5'), --CH₂ --CO--CH₃ or --CH₂--CH₂ --CN;in which R^(5') represents methyl or ethyl; B represents--CH₂ --, --O-- or a direct bond;optionally in the form a racemicmixture or a pure enantiomer thereof, and/or of a pharmaceuticallyutilizable hydrate or acid addition salt, alkali metal salt, alkalineearth metal salt, silver salt or guanidinium salt thereof.
 2. A compoundof the formula (I) according to claim 1, in whichR¹ represents hydrogenor C₁ -C₃ -alkyl which is optionally substituted by hydroxyl, R²independently of R¹ represents hydrogen or methyl, R³ representshydrogen, methyl or ethyl, R^(3') represents hydrogen or methyl, R⁴represents hydrogen, alkyl having 1 to 4 carbon atoms which isoptionally substituted by hydroxyl, methoxy, amino, methylamino ordimethylamino, or represents (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl, X¹represents hydrogen, fluorine or chlorine, Z represents radicals of thestructures ##STR77## in which R⁷ represents hydrogen, hydroxyl, --NR¹⁰R¹¹, hydroxymethyl or --CH₂ --NR¹⁰ R¹¹,where R¹⁰ represents hydrogen, C₁-C₂ -alkyl which is optionally substituted by hydroxyl, or representsalkoxycarbonyl having 1 to 4 C atoms in the alkoxy moiety, or C₁ -C₃-acyl, R¹¹ represents hydrogen or methyl, R⁸ represents hydrogen,straight-chain or branched C₁ -C₃ -alkyl or cyclopropyl, R⁹ representshydrogen or methyl, R⁵ represents hydrogen or methyl, R⁶ representshydrogen, and B represents --CH₂ --, O or a direct bond.
 3. A compoundof the formula (I) according to claim 1, in whichR¹ represents hydrogenor methyl, R² represents hydrogen, R³ represents methyl or ethyl, R^(3')represents hydrogen or methyl, R⁴ represents hydrogen, methyl or ethyl,X¹ represents fluorine, Z represents radicals of the structures##STR78## in which R⁷ represents hydrogen, hydroxyl, --NR¹⁰ R¹¹,hydroxymethyl or --CH₂ --NR¹⁰ R¹¹,where R¹⁰ represents hydrogen, methyl,alkoxycarbonyl having 1 to 4 C atoms in the alkoxy moiety or C₁ -C₃-acyl, R¹¹ represents hydrogen or methyl, R⁸ represents hydrogen,straight-chain or branched C₁ -C₃ -alkyl or cyclopropyl, R⁶ representshydrogen, R⁹ represents hydrogen or methyl, R⁵ represents hydrogen ormethyl, and B represents --CH₂ --, O or a direct bond.
 4. Anantibacterial composition comprising a antibacterially effective amountof a compound of formula (I) according to claim 1 and a pharmaceuticallyacceptable carrier.
 5. A method of preventing or combatting a bacterialinfection in a patient comprising administering to said patient anantibacterially effective amount of a compound of formula (I) accordingto claim
 1. 6. A process for preparing a compound of the formula (I)according to claim 1, said process comprising reacting a compound of theformula (II): ##STR79## in which R¹, R², R³, R^(3'), R⁴ and X¹ have theineaning given in claim 10; andX² represents halogen;with a compound ofthe formula (III):

    Z--H                                                       (III)

in which Z has the meaning given in claim 10;optionally in the presenceof an acid scavenger.
 7. The process according to claim 6, wherein X²represents fluorine or chlorine.